The current methods for preparing (8S)-8-fluoroerythromycins involve either treatment of 8,9-anhydroerythromycin 6,9-hemiacetals or their N-oxides with fluorinating agents such as perchloryl fluoride, fluoroxyperfluoroalkanes, fluoroxysulfurpentafluoride, molecular fluorine, lead tetracetate/hydrogen fluoride or trifluoroacetylhypofluorite (U.S. Pat. No. 4,514,562). More recently, the preparation of (8S)-8-fluoroerythromycins has been improved by exposure of erythromycin to perchloryl fluoride in an acetic acid buffer and an inert co-solvent (U.S. Pat. No. 4,673,736). The aforementioned fluorinating agents have disadvantages; such as: hazards in handling, relatively high cost, the need for special reaction vessels, and chemical instability, which make them unsatisfactory for preparing commercial quantities of (8S)-8-fluoroerythromycins. Perchloryl fluoride, in particular, is known to form unstable and explosive organoperchlorates in reactions with organic molecules. See Peet, H. H. J. and Rocket, B. W. J. Organometal. Chem. 82, C57 (1974) and Adcock, W. and Khor, J. C. ibid. 91, C20 (1975).
N-F (electrophilic) fluorinating agents, characterized by a structure containing an N-F bond, are a well known class of reagents for introducing fluorine into organic molecules. As a class, they have been shown to be stable due to their ability to be stored for long periods of time and high melting points and are easily handled reagents.
The fluorination of double bonds in various organic compounds with N-F fluorinating agents is reported in J. Am. Chem. Soc. 112, 8563 (1990) and J. Org. Chem. 1993, 58, 2791-2796. The conditions reported for such N-F fluorinations include use of an organic solvent such as acetonitrile, dichloromethane and tetrahydrofuran and an oxygen containing nucleophilic reagent such as acetic acid. When these standard N-F fluorination conditions were used to attempt to fluorinate 8-fluoroerythromycin or 8,9-anhydroerythromycin, poor yields of 8S-8-fluoroerythromycins were obtained.